US3551431A - Isonipecotonitriles - Google Patents

Isonipecotonitriles Download PDF

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Publication number
US3551431A
US3551431A US739194A US3551431DA US3551431A US 3551431 A US3551431 A US 3551431A US 739194 A US739194 A US 739194A US 3551431D A US3551431D A US 3551431DA US 3551431 A US3551431 A US 3551431A
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United States
Prior art keywords
acid
isonipecotonitrile
ether
solution
phenylethyl
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Expired - Lifetime
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US739194A
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English (en)
Inventor
Hans Herbert Kuhnis
Rolf Denss
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Novartis Corp
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Geigy Chemical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • R is allyl or propinyl and their addition salts with inorganic and organic acids, have valuable pharmacological properties, in particular antitussive activity with, at the same time, a favourable therapeutic index.
  • the antitussive activity of the compounds of general Formula I for instance the hydrochlorides of I-(Z-phenylethyl)-4-allyl isonipecotonitrile, 1-(2-phenylethyl)-4-(2- propinyl)-isonipecotonitrile, 1 (3-phenylpropyl)-4-allyl isonipecotonitrile and 1-(3-phenylpropyl)-4-(2-propinyl)- isonipecotonitrile, can be demonstrated, e.g., on intravenous administration in the cat by the method according to R. Domenjoz, Arch. exp. Path. und Pharmakol. 215, 19-24 (1952).
  • Another method for provingthe antitussive activity is the determination of the tussive irritation in the guinea pig, caused by sulphur dioxide, by subcutaneous or oral administration of the test substances.
  • male guinea pigs in a perspex chamber were exposed at atmospheric pressure to an SO /CO /air mixture at a constant ratio of 20 ml.:1.5 litres:l0.5 litres per minute until the onset of cough or for a maximum of 120 seconds. The onset of cough was assessed visually.
  • the guinea pigs reacting with cough were put in groups of 6 animals each.
  • the new piperidine derivatives of general Formula I and their pharmaceutically acceptable acid addition salts are suitable as active substances for pharmaceutical preparations for the treatment of coughs, particularly for the amelioration and relief of tussive irritation. They can be administered orally, rectally or parenterally to warmblooded animals, particularly mammals.
  • an amide of the general Formula II i 1120 CH2 R1 (II) wherein R and R have the meanings given in Formula I is reacted with an agent spliting off water and, if desired, the compound obtained of the general Formula I is converted into an addition salt with an inorganic or organic acid.
  • Thinoyl chloride, phosphorus trichloride and phosphorus pentoxide are mentioned as examples of agents which split off water.
  • the water is split oif, e.g., by boiling an amide of the general Formula II with thionyl chloride in benzene or chloroform or by heating with phosphorus pentoxide, preferably at temperatures between and 200, or by heating with phosphorus trichloride.
  • Formula IV 1120 CHz wherein Y6 represents an alkali metal ion, particularly lithium ion and R, has the meaning given in Formula I, in an inert organic solvent with a reactive ester of allyl alcohol or 2-propin-1-ol and, if desired, converting the compound obtained of general Formula I into an addition salt with an inorganic or organic acid.
  • reactive esters of the allyl alcohol or 2-propin-1-ol particularly the halides such as the bromide, iodide and chloride, also alkane and arene sulphonic acid esters such as methane or p-toluene sulphonic acid esters, are used.
  • the halides such as the bromide, iodide and chloride
  • alkane and arene sulphonic acid esters such as methane or p-toluene sulphonic acid esters
  • a mixture of abs. diethyl ether or tetrahydrofuran with 1,2-dimethoxyethane (ethylene glycol dimethyl ether) is suitable as reaction medium for the main reaction.
  • the alkali metal compounds of general Formula IV are produced in situ from other suitable alkali metal compounds.
  • Triphenylmethyl lithium which is particularly suitable as such, is also preferably formed in situ from another organic lithium compound such as phenyl lithium, for
  • triphenylmethane in 1,2- dimethoxyethane
  • triphenylmethyl lithium produces intensively coloured solutions, its formation as well as its use can be easily followed by the isonipecotonitrile which is subsequently added.
  • triphenylmethyl sodium or potassium for example, can be useful instead of triphenylmethyl lithium.
  • the steps in the processes according to the invention are generally slightly exothermic and can be performed at room temperature or slightly raised temperature. If necessary, the reaction mixture must also be able to be cooled depending on the starting materials and amounts thereof used.
  • compounds of general Formula I wherein R is the allyl group, and their addition salts with inorganic and organic acids are produced by a third process by treating a compound of the restricted general .
  • Formula V which is already embraced by general Formula I and in which R has the meaning given in Formula I, with hy drogen until the equimolar amount has been taken up, in the presence of a catalyst suitable for the partial hydrogenation of triple bonds.
  • catalyst e.g., palladium on CaCO partially deactivated with lead acetate, in ethanol as solvent and further deactivated in situ by the addition of quinoline (Lindlar catalyst, cf. Helv. Chim. Acta 35, 450 (1952)), is used.
  • the compound obtained of general Formula I is converted into an addition salt with an inorganic or organic acid.
  • the piperidine derivatives of the general Formula I obtained by the processes according to the invention are then converted into their addition salts with inorganic and organic acids in the usual way.
  • the acid desired as salt component or a solution thereof is added to a solution of a piperidine derivative of the general Formula I in an organic solvent such as diethyl ether, methanol or ethanol, and the salt which precipitates either direct or after addition of a second organic liquid, e.g. diethyl ether to methanol, is isolated.
  • salts for use as active substances in therapeutic compositions, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with those acids the anions of which have no pharmacological action or which in themselves have a desired pharmacological action.
  • salts to be used as active substances crystallise well and are not or are only slightly hygroscopic.
  • Hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, fi-hydroxy-ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid, embonic acid, or 1,5-naphthalene disulphonic acid, for example, can be used for salt formation with piperidine derivatives of the general Formula I.
  • the new piperidine derivatives of the general Formula I and their salts may be administered orally, rectally or parenterally.
  • the daily dosages of free bases or of pharmaceutically acceptable salts thereof vary between about 0.02 mg./kg. and about mg./kg., preferably about 0.05 mg./kg. to about 5.0 mg./kg. for mammals, depending on the mammal and condition.
  • Suitable dosage units such as drages (sugar-coated tablets), capsules, tablets, suppositories or ampoules, preferably contain 1-100 mg. of piperidine derivative of the general Formula I or of a pharmaceutically acceptable salt thereof.
  • Dosage units for oral administration preferably contain between 1% and of a piperidine derivative of general Formula I or of a pharmaceutically acceptable salt thereof as active substance. They are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose sucrose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores.
  • solid, pulverulent carriers such as lactose sucrose, sorbitol, mannitol
  • starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder
  • cellulose derivatives or gelatine optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols
  • the latter are coated, e.g., with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents.
  • Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.
  • Other suitable dosage units for oral administration are hard gelatine capsules and also soft, closed capsules made of gelatine and a softener such as glycerin.
  • the former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium metabisulphite or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilisers can also be added.
  • lozenges for the treatment of coughs, e.g., lozenges as well as forms not made up into single dosages can be used for oral administration, e.g., cough syrups or drops prepared with the usual auxiliaries.
  • Dosage units for rectal administration are, e.g., suppositories which consist of a combination of a piperidine derivative of the general Formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance with polyethylene glycols.
  • Ampoules for parenteral, particularly intramuscular, also intravenous, administration preferably contain a water-soluble salt of a piperidine derivative of the general Formula I as active substance in a concentration of, preferably, 0.5-5%, in aqueous solution, optionally together with suitable stabilisers and buffer substances.
  • (c) 1,000 capsules each containing 10 mg. of active substance are produced as follows: 10 g. of 1-(2-pheny1- ethyl)-4-allyl isonipecotonitrile hydrochloride are mixed with 263 g. of lactose. The mixture is evenly moistened with an aqueous solution of 2 g. of gelatine and granulated through a suitable sieve (e.g. sieve III, Ph. Helv. V). The granulate is mixed with g. of dried maize starch and g. of talcum and is then evenly filled into 1,000 hard gelatine capsules, size 1.
  • a suitable sieve e.g. sieve III, Ph. Helv. V
  • a cough syrup containing 0.5% active substance is prepared as follows: 1.5 litres of glycerin, 42 g. of p-hydroxybenzoic acid methyl ester, 18 g. of p-hydroxybenzoic acid n-propyl ester and, while slightly warming, 50 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride are dissolved in 3 litres of distilled water. 4 litres of 70% sorbitol solution, 1,000 g. of crystallised sucrose, 350 g. of glucose and a flavouring, e.g. 250 g. of Orange Peel Soluble Fluid produced by Ely Lilly & Co., Indianapolis, or 5 g. of natural lemon flavouring and 5 g. of Halb und Halb essence, both produced by Haarmann und Reimer, Holzminden, Germany, are added. The solution obtained is filtered and the filtrate is made up to 10 litres with distilled water.
  • a cough syrup containing 0.25% of active substance is produced as follows: 25 g. of 1-(2-phenylethyl)- 4-allyl isonipecotonitrile hydrochloride is dissolved by warming in a mixture of 2.5 litres of water, and 0.5 litre of 96% ethanol. Also, a syrup is made from 30 litres of water, 1 litre of 70% sorbitol solution, 3,000 g. of crystallised sucrose, 42 g. of p-hydroxybenzoic acid methyl ester and 18 g. of p-hydroxybenzoic acid n-propyl ester, and this syrup is carefully mixed with the solution of active substance. After the addition of flavourings, e.g. those mentioned under (d) and, if necessary, filtration, the syrup obtained is made up to 10 litres with distilled Water.
  • flavourings e.g. those mentioned under (d) and, if necessary, filtration
  • drops containing 2.5% of active substance are prepared by dissolving 250 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride and 30 g. of sodium cyclamate in a mixture of 4 litres of 96% ethanol and 1 litre of propylene glycol. Also, 3.5 litres of 70% sorbitol solution are mixed with 1 litre of water and this mixture is added to the above solution of active substance.
  • a mass for suppositories is made from 2.5 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride and 167.5 g. of Adeps solidus and 100 suppositories are filled therewith. Each contain 25 mg. of active substance.
  • EXAMPLE 2 4.5 g. of bromobenzene in 60 ml. of abs. ether are placed in a 200 ml. four-necked flask and, while stirring under an atmosphere of nitrogen, 0.40 g. of lithium wire cut into small pieces are added whereupon the ether be gins to boil. After the reaction has subsided the mixture is refluxed for another 2 /2 hours. 6.35 g. of triphenylmethane in 25 ml. of abs. 1,2-di-methoxyethane are added all at once to the solution of phenyl lithium obtained whereupon, due to the formation of triphenylmethyl lithium, the solution turns deep red and gently boils. After stirring for 20 minutes at room temperature, 5.5 g.
  • the acid extracts are made alkaline and exhaustively extracted with chloroform.
  • the chloroform extracts are dried and concentrated.
  • the residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled.
  • the 1-(2 phenylethyl)-4-allyl isonipecotonitrile boils at 126-139/0.2 torr.
  • the hydrochloride prepared with hydrogen chloride in ether melts, after recrystallisation from methanol, at M.P. 293294.
  • the starting material is produced as follows:
  • Ether is added to the residue and the ether solution obtained is extracted four times with dilute hydrochloric acid.
  • the acid extracts are made alkaline ond exhaustively extracted with chloroform.
  • the chloroform extracts are dried and evaporated.
  • the residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled.
  • the 1-(2-phenylethyl)-4(2-propinyl)-isonipecotonitrile passes over at 141-170/ 0.05 torr.
  • the hydrochloride is produced therefrom in ether and recrystallised from isopropanol/methanol.
  • EXAMPLE 4 A solution of 2.52 g. of l-(2-phenylethyl)-4-(2- propinyl)-isonipecotonitrile in 50 ml. of ethanol is hydrogenated at room temperature under normal pressure in the presence of 0.5 g. of Lindlar catalyst (palladium on calcium carbonate, partially deactivated with lead acetate) and 0.2 g. of quinoline. After about 107% of the theoretically necessary amount of hydrogen has been taken up, the hydrogenation is discontinued, the catalyst is filtered off and thoroughly washed with ethanol. The filtrate is evaporated in a rotary evaporator and the residue is distilled under high vacuum.
  • Lindlar catalyst palladium on calcium carbonate, partially deactivated with lead acetate
  • the l-(2-phenylethyl)-4- allyl isonipecotonitrile obtained boils at l26-139/0.2 torr.
  • the hydrochloride prepared with hydrogen chloride is recrystallised from methanol whereupon it melts at 293-294".

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US739194A 1967-06-28 1968-06-24 Isonipecotonitriles Expired - Lifetime US3551431A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NO16881567 1967-06-28
NO16881667 1967-06-28
CH42068A CH491915A (de) 1967-06-28 1968-01-11 Verfahren zur Herstellung von neuen Piperidinderivaten

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US3551431A true US3551431A (en) 1970-12-29

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US739194A Expired - Lifetime US3551431A (en) 1967-06-28 1968-06-24 Isonipecotonitriles

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US (1) US3551431A (enrdf_load_stackoverflow)
BE (1) BE717270A (enrdf_load_stackoverflow)
CH (1) CH491915A (enrdf_load_stackoverflow)
ES (1) ES355551A1 (enrdf_load_stackoverflow)
FR (2) FR1596472A (enrdf_load_stackoverflow)
GB (1) GB1231081A (enrdf_load_stackoverflow)
IL (1) IL30265A0 (enrdf_load_stackoverflow)
NL (1) NL6808702A (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4870086A (en) * 1986-01-03 1989-09-26 Astra Lakemedel Aktiebolag Optically pure compound and a process for its preparation
US20040071797A1 (en) * 2002-10-09 2004-04-15 Dennis Donald P. Method and formulation for suppressing mold
US10150731B2 (en) * 2015-01-16 2018-12-11 Bayer Cropscience Aktiengesellschaft Method for preparing 4-cyanopiperidine hydrochloride

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4870086A (en) * 1986-01-03 1989-09-26 Astra Lakemedel Aktiebolag Optically pure compound and a process for its preparation
US20040071797A1 (en) * 2002-10-09 2004-04-15 Dennis Donald P. Method and formulation for suppressing mold
US10150731B2 (en) * 2015-01-16 2018-12-11 Bayer Cropscience Aktiengesellschaft Method for preparing 4-cyanopiperidine hydrochloride

Also Published As

Publication number Publication date
CH491915A (de) 1970-06-15
FR1596472A (enrdf_load_stackoverflow) 1970-06-22
GB1231081A (enrdf_load_stackoverflow) 1971-05-05
FR7917M (enrdf_load_stackoverflow) 1970-05-11
NL6808702A (enrdf_load_stackoverflow) 1968-12-30
ES355551A1 (es) 1970-03-01
BE717270A (enrdf_load_stackoverflow) 1968-12-27
IL30265A0 (en) 1968-08-22

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